1. Gastropathies of autoimmune origin
Enzo Ierardi
Sezione di Gastroenterologia
Dipartimento delle Scienze Mediche e del Lavoro
Università degli Studi di Foggia

2. Gastropathies of autoimmune origin
historical antecedents
outstanding discoveries
unresolved problems
Whittingham & MacKay, Int Rev Immunol. 2005

3. historical antecedents
The earliest recorded history of autoimmune gastritis can be traced to 1849 in London, when Thomas Addison described "a very remarkable form of anemia" later called pernicious anemia
This was followed by the recognition of a gastric mucosal defect suspected to have a nutritional basis

4. historical antecedents
discovery of:
the megaloblast that characterized the anemia
insufficiency of a dietary extrinsic factor characterized as vitamin B12 (cobalamin)
treatment with vitamin B12 proved curative
gastric-secreted intrinsic factor

5. outstanding discoveries
The link between pernicious anemia and gastritis/atrophy was first confirmed:
histologically after immediate fixation of the stomach postmortem
later, in the 1940s, by peroral tube biopsy
The causes of gastritis remained enigmatic until the era of autoimmunity, when:
autoantibodies were detected first to gastric intrinsic factor
then to gastric parietal cells

6. outstanding discoveries
Hints of a dichotomy in pathogenesis of gastritis were clarified by the description in 1973 of Type A (Autoimmune) and Type B gastritis of unknown origin
Clarification was enhanced by identification in Type A gastritis of the autoantigen of the parietal cell antibody, by the alpha and beta subunits of gastric H+/K+ ATPase

7. outstanding discoveries
Type B gastritis causative role of gastric infection with Helicobacter pylori
Warren & Matshall, 1983
Experimental autoimmune gastritis: mouse models of human organ-specific autoimmune disease
Field et al, 2005

8. Animal model Lymphnodes Th1
The disease is induced in the regional gastric lymph node (pathogenic CD4+ T cells are recruited)
Regulation by CD4+CD25+T cells, and removal of such regulatory cells by neonatal thymectomy is the major mechanism by which disease can develop
The culprit T helper type 1 (Th1) CD4+ T cells recognize either the alpha- or beta-subunits of the gastric H+/K+ ATPase
The beta-subunit appears to be the initiating autoantigen, while the alpha-subunit may have a role in perpetuating disease
Lymphnodes
Th1

9. Animal model
thymus
The two subunits of the gastric H/K ATPase, i. e. the catalytic alpha-subunit and the glycoprotein beta-subunit, are the major targets of parietal cell autoantibodies associated with human and murine autoimmune gastritis
The beta-subunit appears to be the initiating autoantigen, while the alpha-subunit may have a role in perpetuating disease
Expression of the gene of gastric H/K-ATPase alpha-subunit in the thymus may explain the dominant role of the beta-subunit in the pathogenesis of autoimmune gastritis
Alderuccio et al, Autoimmunity, 1997
Th1

10. ­ ¯ patterns of Type B gastritis HCl Site - duodenal gastric absent
Antrum – 80%
Antrum + Body
20%
Gastric
pathology
HCl
output
Duodenal
peptic
disease -
Chronic active
gastritis
- atrophy
- intestinal
metaplasia
duodenal
gastric
- duodenitis
- gastric
Dixon
,1994

11. ¯ pattern of Type A gastritis HCl Site risk carcinoma absent output
gastric
pathlogy
HCl
output
duodenal
diseases
risk
- atrophy
intestinal
metaplasia
carcinoma
Body

12. GASTRITIS – CARCINOMA SEQUENCE
intestinal metaplasia
and atrophy
carcinoma
Correa, 1993
Both Type A (100%) and Type B (20%) gastritis are precancerous conditions

13. antibodies to parietal cells
unresolved problems
Type B gastritis and immunity
Helicobacter pylori
 “antigenic mimicry”
antibodies to parietal cells 
atrophy
Negrini, Gastroenterology

14. unresolved problems
IMMUNOHISTOCHEMICAL REACTION OF HP+ SERUM WITH AUTOLOGOUS PARIETAL CELLS

15. unresolved problems
Increased values of incidence and prevalence of Helicobacter pylori infection in geographic areas with high diffusion of gastric carcinoma
Forman, 1990 (Cina)
Chen, 1990 (Colombia)
Increased risk of gastric carcinoma in patients who aquire Helicobacter pylori in pediatric age
Sipponen, 1993

16. unresolved problems
Autoantibodies reacting with gastric antigens in Helicobacter pylori associated body gasritis in dyspeptic children Ierardi, 1998 ?
The H. pylori related autoreaction to gastric mucosa could be followed by the appearance of circulating autoantibodies to parietal cells thus suggesting a sequential link between types B and A gastritis
The H. pylori related autoreaction in the stomach and the presence of serum autoantibodies to parietal cells are indipendent phenomena expressed in different types of gastritis

17. unresolved problems
HP related gastric atrophy as result of cross reaction to parietal cells
target of reaction represented by canalicular H+/K+ ATPase protonic pump
Appelmelk,
Faller,

18. H. PYLORI AND AUTOIMMUNITY
unresolved problems
H. PYLORI AND AUTOIMMUNITY
It is possible that the long-term damage of infected mucosa may expose to immune system even "self" components
Bacterial “soma” exposes to immune system blood Lewis x ed y antigens, which are absolutely similar to that of protonic pump ATPase and mucin
Once atrophy has developed, bacteria show the tendency to disappear and antibody titres reach the level of seronegativity
In this phase phenomena of autoimmunity or malignacy may appear and be sustained independently by the initial antigenic stimulus
Torelli, 2006

19. LOW GRADE MALT GASTRIC LYMPHOMA
unresolved problems
LOW GRADE MALT GASTRIC LYMPHOMA
B lymphocytes (atypic clones) with tendency to diffuse in the lamina propria and epithelium

20. MALT LYMPHOMA MEETS H. PYLORI
Hp in more than 90% of primary gastric lymphomas
Hp associated to the development of lymphoid aggregates with germinal centres (MALT tissue)
MALT is not found in a normal stomach !!!!!
Wotherspoon et al, Lancet 1991

21. EVIDENCES FOR A ROLE OF H. PYLORI IN MALT LYMPHOMA
Epidemiologic
Experimental
Clinic

22. Experimental evidences
Th1 B
Crabtree et al, Lancet 1993
Tumoral immunoglobulins

23. “tumoral immunoglobulins”
Immunoglobulins with heavy chains (IgH)
May be identified in paraffin embdedded tissues by a PCR method described by Wan et al in 1992 (J Clin Pathol)
Five successive studies confirmed its sensitivity and suitability (Algara 1993, Ling 1993, Diss 1994, De Re 1995 e Lozano 1996)

24. Pattern of tumoral immunoglobulins
unresolved problems
Pattern of tumoral immunoglobulins B
Th1
AUTOIMMUNITY (?)
Spencer et al, J Pathol 1990
Griner et al, Lab Invest 1994

25. Chronic erosions of the stomach
unresolved problems
Chronic erosions of the stomach
Erosions which arise on mucosal nodular elevations, oftel located in the antrum, not suitable of bleeding and often characterized by absenct or dyspeptic symptoms
Elta, 1986
Invoked causes: H. pylori, chemical injury due to bile reflux or NSAIDs (Type C gastritis), chronic ischaemia

26. FOOD SENSITIZATION AND RECURRENCE FREQUENCY IN PATIENTS WITH CHRONIC GASTRIC EROSIONS
among significant factors in pathogenesis of chronic gastric erosions, the infectious-allergic factor is essential
high titers of specific IgE antibodies to infectious, home, food and plant allergens are found
persistence in remission of high and moderate titers of specific IgE indicated chronicity of the disease and expected recurrence
Sboichakov et al, 2002
Humoral and cellular responses to cow milk proteins in patients with milk-induced IgE-mediated and non-IgE-mediated disorders
Shelk et al, Allergy 2005

27. Gastropathies of autoimmune origin and uncertain clinical significance
unresolved problems
Gastropathies of autoimmune origin and uncertain clinical significance
Lymphocytic gastritis (celiac disease)
Eosiniphilic gastroenteritis
Others